Stress has been implicated as an important environmental factor, that interacts with genetic based vulnerabilities, in the etiology and manifestation of a variety of mental disorders. A great deal is known about the influence of stress on the adult brain in laboratory animals. However, relatively less is known about the consequences that early stress exerts on the brain that persist to adulthood. Such long-lasting adaptations (or maladaptations) to early stress could contribute to the increased sensitivity of an individual organism to later stressful events or other perturbations. Other Projects described in this Center proposal focus on characterizing the influence of early stress, and genetic models of predisposition to stress, on neurotransmitter and receptor systems of the adult animal, particularly monoaminergic system and certain peptide systems. The objective of this Project is to extend these studies to the arena of post-receptor mechanisms. Neurotransmitters and their receptors are known to produce their myriad effects on target neurons via complex cascades of intracellular messengers. Among the consequences of perturbing these intracellular messenger pathways are alterations in the regulation of gene expression. Obviously, such alterations are of particular relevance to this Center: adaptations at the level of gene expression represent plausible mechanisms for long-lasting neural plasticity in response to early stress. We have previously identified effects of repeated stress on the cAMP signal transduction pathway and some of its target proteins in specific brain regions of adult rats. The objective of this Project is to study the ways in which early life stress modifies this signaling pathway in the adult and thereby alters the adult's responsiveness to subsequent stressors and other perturbations. We will also study whether lines selectively bred for vulnerability to stress-related phenomena show similar adaptations in the same signaling pathways. These studies will contribute to the Center's overall goal of better understanding the long-lasting effects of early stress and the role of genetic predisposition to stress on brain function and behavior.